Novel and high efficiency anti-addiction drug

A drug and addiction technology, applied in the field of new high-efficiency anti-addiction drugs, can solve problems such as side effects, large individual differences of thienorphine, and limited clinical application

Active Publication Date: 2018-09-14
TEIZHOU HUAYUAN MEDICINAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, thienorphine varies greatly among individuals and has obvious side effects, which limits its clinical application.

Method used

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  • Novel and high efficiency anti-addiction drug
  • Novel and high efficiency anti-addiction drug
  • Novel and high efficiency anti-addiction drug

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0028] 1.7 Thienomorphine (C 1 ) preparation

[0029] 1.2g (2mmol) vii 1 Dissolve in 5ml of anhydrous tetrahydrofuran, add 2ml of 2M LiAlH dropwise under stirring 4 Tetrahydrofuran solution; after adding, stir overnight at room temperature; then add magnesium sulfate heptahydrate in batches until no gas is released. Filtrate, evaporate the filtrate to dryness under reduced pressure, separate by silica gel column chromatography, elute with petroleum ether: dichloromethane: methanol = 4: 1: 0.1, collect the required components, and recrystallize with methanol to obtain C 1 0.75g; Dissolve this solid with ethanol, add hydrogen chloride ether solution, to pH2, stir, precipitate solid, after standing overnight, filter and wash with anhydrous ether to obtain C 1 ·HCl 0.61g, melting point: >200°C. 1 H-NMR (400MHz, DMSO-d6): 9.62 (br, 1H); 9.39 (br, 1H); 7.26 (m, 1H); 7.01 (d, 1H); 6.91 (m, 1H); 1H); 6.55(d, 1H); 4.64(br, 1H); 4.54(s, 1H); 3.90(d, 1H); 3.41(s, 3H); 3.28(m, 2H); 3...

Embodiment 1

[0036] Example 1 (2S)-2-[(5R, 6R, 7R, 14S)-N-(cyclopropyl-dideuteriomethyl)-4,5-epoxy-6,14-ethylene- 3-Hydroxy-6-methoxymorphinan-7-yl]-4-(thiophen-2-yl)-butan-2-ol (I 1 ) preparation

[0037]

[0038] With reference to the method of reference example 1.7, vii 1 with LiAlD 4 (% D: > 98) reaction, makes I 1 ; will I 1 Dissolve in ethanol, form a salt with hydrogen chloride, and obtain I 1 · HCl, melting point: >200°C. 1 H-NMR (400MHz, DMSO-d6): 9.60 (br, 1H); 9.34 (br, 1H); 7.26 (m, 1H); 7.00-6.90 (m, 2H); 6.73 (d, 1H); d, 1H); 4.64(br, 1H); 4.54(s, 1H); 3.90(d, 1H); 3.30-2.30(m, 7H); 2.28(m, 1H); 1.96(m, 2H); 1.82 (m, 2H); 1.70(m, 1H); 1.51(m, 1H); 1.47(m, 1H); 1.35(m, 1H); 1.30(s, 3H); 1.13(m, 1H); 0.67( m, 2H); 0.58(m, 2H); 0.39(m, 1H).

Embodiment 2

[0039] Example 2 (2S)-2-[(5R, 6R, 7R, 14S)-N-(cyclopropyl-dideuteromethyl) 4,5-epoxy-6,14-ethylene-3 Preparation of -Hydroxy-6-methoxymorphinan-7-yl]-4-(thiophen-3-yl)-butan-2-ol ()

[0040]

[0041] With reference to the method of reference example 1.7, vii 2 with LiAlD 4 (% D: > 98) reaction, makes I 2 ; will I 2 Dissolve in ethanol, form a salt with hydrogen chloride, and obtain I 2 HCl, H NMR spectrum: 1 H-NMR (400MHz, DMSO-d6): 9.66 (br, 1H); 9.37 (br, 1H); 7.43-7.02 (m, 3H); 6.73 (d, 1H); 6.55 (d, 1H); 4.64 ( br, 1H); 4.54(s, 1H); 3.90(d, 1H); 3.28-2.79(m, 7H); 2.26(m, 1H); 1.95-1.70(m, 5H); 2H); 1.37(m, 1H); 1.32(s, 3H); 1.12(m, 1H); 0.36(m, 1H); 0.59(m, 2H); 0.68(m, 2H).

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Abstract

The invention relates to a compound of structural formula (I) and a non-toxicity pharmaceutically acceptable salt thereof, wherein R represents H or an alkyl group with 1 to 3 carbon atoms; the purpose of any compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is to prepare a drug for treating an addiction disease; and the addiction disease is selected from cocaine addiction, methylamphetamine type drug addiction, opium type drug or medicine addiction, alcoholic addiction, smoking addiction or ketamine addiction.

Description

technical field [0001] The present invention relates to novel deuterated N-cyclopropylmethyl-noripavine derivatives or pharmaceutically acceptable salts thereof with anti-addiction effects, pharmaceutical compositions containing these compounds as active ingredients, and the Derivatives or pharmaceutically acceptable salts thereof are used in the preparation of drugs for detoxification. Background technique [0002] Drug abuse and addiction seriously threaten human physical and mental health. Thienorphine has a strong antagonism to morphine, and is being used in clinical research for the treatment of opioid addiction. However, thienorphine varies greatly among individuals and has obvious side effects, which limit its clinical application. [0003] [0004] The object of the present invention is to provide thienorphine analogues that are orally effective and have better morphine antagonism. Contents of the invention [0005] The present invention provides compounds re...

Claims

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Application Information

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IPC IPC(8): C07D489/12A61K31/485A61P25/30A61P25/32A61P25/34
CPCC07D489/12
Inventor 仲伯华付仁芳杨家俊
Owner TEIZHOU HUAYUAN MEDICINAL TECH CO LTD
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